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Aldehyde Dehydrogenase 2 Mediates Alcohol-Induced Colorectal Cancer Immune Escape through Stabilizing PD-L1
Hong Zhang1, Yuhui Xia1, Fang Wang1
1Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Esophageal Cancer Institute Guangzhou 510060 China.
Abstract:
Despite the great success of immunotherapy in a small subset of cancer patients, most colorectal cancer (CRC) patients do not respond to programmed cell death receptor 1 (PD-1) blockade immunotherapy. There is an urgent medical need to elucidate how cancer cells evade immune response and to develop novel means to boost the efficacy of immune checkpoint inhibitors. In this study, alcohol induces ligand programmed cell death receptor 1 (PD-L1) expression of CRC cells in vitro and in vivo. Alcohol exposure is shown to induce aldehyde dehydrogenase 2 (ALDH2) expression that is a crucial enzyme involved in alcohol metabolism, and low level of lymphocytes infiltration in the murine CRC model and patients. Intriguingly, ALDH2 and PD-L1 protein expression are positively correlated in tumor tissues from the CRC patients. Mechanistically, ALDH2 stabilizes PD-L1 protein expression by physically interacting with the intracellular segment of PD-L1 and inhibiting its proteasome-dependent degradation mediated by an E3 ubiquitin ligase Speckle Type POZ Protein (SPOP). Importantly, inhibition of ALDH2 reduces PD-L1 protein in CRC cells and promotes tumor-infiltrating T cells (TILs) infiltration, presumably leading to the significant potentiation of anti-PD-1 antibody efficacy in a mouse CT26 CRC model. The findings highlight a crucial role played by ALDH2 to facilitate alcohol-mediated tumor escape from immunity surveillance and promote tumor progression.
Insights
Alcohol promotes colorectal cancer immune evasion by increasing PD-L1 expression via ALDH2. Inhibiting ALDH2 reduces PD-L1, enhances T-cell infiltration, and improves immunotherapy response in preclinical models.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Most colorectal cancer (CRC) patients do not respond to PD-1 blockade immunotherapy.
- Understanding mechanisms of immune evasion is critical for improving CRC treatment.
- Novel strategies are needed to enhance immune checkpoint inhibitor efficacy.
Purpose of the Study:
- To investigate the role of alcohol in colorectal cancer immune evasion.
- To elucidate the mechanism by which alcohol affects PD-L1 expression in CRC.
- To explore ALDH2 as a therapeutic target for enhancing immunotherapy.
Main Methods:
- In vitro and in vivo studies using CRC cell lines and a murine CRC model.
- Analysis of ALDH2 and PD-L1 expression in patient tumor tissues.
- Investigation of the interaction between ALDH2 and PD-L1 using biochemical assays.
- Assessment of anti-PD-1 antibody efficacy following ALDH2 inhibition in a mouse model.
Main Results:
- Alcohol exposure increases PD-L1 expression in CRC cells.
- Alcohol induces ALDH2 expression, which stabilizes PD-L1 by inhibiting its degradation.
- ALDH2 and PD-L1 expression are positively correlated in CRC patient tumors.
- ALDH2 inhibition reduces PD-L1, increases T-cell infiltration, and potentiates anti-PD-1 therapy efficacy in a mouse model.
Conclusions:
- ALDH2 plays a key role in alcohol-mediated immune evasion in colorectal cancer.
- Targeting ALDH2 represents a promising strategy to overcome resistance to PD-1 blockade immunotherapy.
- ALDH2 inhibition can enhance anti-tumor immunity and improve treatment outcomes for CRC patients.
